The major acute-phase protein, serum amyloid P component, in mice is not involved in endogenous resistance against tumor necrosis factor alpha-induced lethal hepatitis, shock, and skin necrosis

The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) induce s lethal hepatitis when injected into D-(+)-galactosamine-sensitized mice o n the one hand or systemic inflammatory response syndrome (SIRS) in normal mice on the other hand. We studied whether serum amyloid P component (SAP), the major acute-phase protein in mice, plays a protective role in both let hal models. For this purpose, we used SAP(0/0) mice generated by gene targe ting. We studied the lethal response of SAP(0/0) or SAP(+/+) mice to both l ethal triggers but found no differences in the sensitivity of both types of mice. We also investigated whether SAP is involved in establishing two typ es of endogenous protection: one using a single injection of interleukin-1 beta (IL-1 beta) for desensitization and clearly involving a liver protein, the other by tolerizing mire for 5 days using small doses of human TNF-alp ha. Although after IL-1 beta or after tolerization the SAP levels in the se rum had risen fourfold in the control mice and not in the SAP(0/0) mice, th e same extents of desensitization and tolerization were achieved. Finally w e observed that the induction of hemorrhagic necrosis in the skin of mice b y two consecutive local injections with TNF-alpha was not altered in SAP(0/ 0) mice. We conclude that the presence or absence of SAP has no influence o n the sensitivity of mice to TNF-alpha-induced hepatitis, SIRS, and hemorrh agic necrosis or on the endogenous protective mechanisms of desensitization or tolerization.